Faculty Bibliography

BACKGROUND:Poor adherence to inhaled medication may lead to inadequate symptom control in patients with respiratory disease. In practice it can be difficult to identify poor adherence. We designed an acoustic recording device, the INCA® (INhaler Compliance Assessment) device, which, when attached to an inhaler, identifies and records the time and technique of inhaler use, thereby providing objective longitudinal data on an individual's adherence to inhaled medication. This study will test the hypothesis that providing objective, personalised, visual feedback on adherence to patients in combination with a tailored educational intervention in a community pharmacy setting, improves adherence more effectively than education alone. METHODS/DESIGN/METHODS:The study is a prospective, cluster randomised, parallel-group, multi-site study conducted over 6 months. The study is designed to compare current best practice in care (i.e. routine inhaler technique training) with the use of the INCA® device for respiratory patients in a community pharmacy setting. Pharmacies are the unit of randomisation and on enrolment to the study they will be allocated by the lead researcher to one of the three study groups (intervention, comparator or control groups) using a computer-generated list of random numbers. Given the nature of the intervention neither pharmacists nor participants can be blinded. The intervention group will receive feedback from the acoustic recording device on inhaler technique and adherence three times over a 6-month period along with inhaler technique training at each of these times. The comparator group will also receive training in inhaler use three times over the 6-month study period but no feedback on their habitual performance. The control group will receive usual care (i.e. the safe supply of medicines and advice on their use). The primary outcome is the rate of participant adherence to their inhaled medication, defined as the proportion of correctly taken doses of medication at the correct time relative to the prescribed interval. Secondary outcomes include exacerbation rates and quality of life measures. Differences in the timing and technique of inhaler use as altered by the interventions will also be assessed. Data will be analysed on an intention-to-treat and a per-protocol basis. Sample size has been calculated with reference to comparisons to be made between the intervention and comparator clusters and indicates 75 participants per cluster. With an estimated 10 % loss to follow-up we will be able to show a 20 % difference between the population means of the intervention and comparator groups with a power of 0.8. The Type I error probability associated with the test of the null hypothesis is 0.05. DISCUSSION/CONCLUSIONS:This clinical trial will establish whether providing personalised feedback to individuals on their inhaler use improves adherence. It may also be possible to enhance the role of pharmacists in clinical care by identifying patients in whom alteration of either therapy or inhaler device is appropriate. REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT02203266 .

This Letter investigated the efficacy of a decision-support system, designed for respiratory medicine, at predicting asthma exacerbations in a multi-site longitudinal randomised control trial. Adherence to inhaler medication was acquired over 3 months from patients with asthma employing a dose counter and a remote monitoring adherence device which recorded participant's inhaler use: n = 184 (23,656 audio files), 61% women, age (mean ± sd) 49.3 ± 16.4. Data on occurrence of exacerbations was collected at three clinical visits, 1 month apart. The relative risk of an asthma exacerbation for those with good and poor adherence was examined employing a univariate and multivariate modified Poisson regression approach; adjusting for age, gender and body mass index. For all months dose counter adherence was significantly (p < 0.01) higher than remote monitoring adherence. Overall, those with poor adherence had a 1.38 ± 0.34 and 1.42 ± 0.39 (remotely monitored) and 1.25 ± 0.32 and 1.18 ± 0.31 (dose counter) higher relative risk of an exacerbation in model 1 and model 2, respectively. However, this was not found to be statistically significantly different. Remotely monitored adherence holds important clinical information and future research should focus on refining adherence and exacerbation measures. Decision-support systems based on remote monitoring may enhance patient-physician communication, possibly reducing preventable adverse events.

INTRODUCTION/BACKGROUND:In clinical practice, it is difficult to distinguish between patients with refractory asthma from those with poorly controlled asthma, where symptoms persist due to poor adherence, inadequate inhaler technique or comorbid diseases. We designed an audio recording device which, when attached to an inhaler, objectively identifies the time and technique of inhaler use, thereby assessing both aspects of adherence. This study will test the hypothesis that feedback on these two aspects of adherence when passed on to patients improves adherence and helps clinicians distinguish refractory from difficult-to-control asthma. METHODS:This is a single, blind, prospective, randomised, clinical trial performed at 5 research centres. Patients with partially controlled or uncontrolled severe asthma who have also had at least one severe asthma exacerbation in the prior year are eligible to participate. The effect of two types of nurse-delivered education interventions to promote adherence and inhaler technique will be assessed. The active group will receive feedback on their inhaler technique and adherence from the new device over a 3-month period. The control group will also receive training in inhaler technique and strategies to promote adherence, but no feedback from the device. The primary outcome is the difference in actual adherence, a measure that incorporates time and technique of inhaler use between groups at the end of the third month. Secondary outcomes include the number of patients who remain refractory despite good adherence, and differences in the components of adherence after the intervention. Data will be analysed on an intention-to-treat and a per-protocol basis. The sample size is 220 subjects (110 in each group), and loss to follow-up is estimated at 10% which will allow results to show a 10% difference (0.8 power) in adherence between group means with a type I error probability of 0.05. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT01529697; Pre-results.

Inhalers are hand-held devices used to treat chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Medication is delivered from an inhaler to the user through an inhalation maneuver. It is unclear whether gender and anthropometric features such as age, height, weight and body mass index (BMI) influence the acoustic properties of inspiratory inhaler sounds and peak inspiratory flow rate (PIFR) in inhalers. In this study, healthy male (n=9) and female (n=7) participants were asked to inhale at an inspiratory flow rate (IFR) of 60 L/min in four commonly used inhalers (Turbuhaler(â„¢), Diskus(â„¢), Ellipta(â„¢) and Evohaler(â„¢)). Ambient inspiratory sounds were recorded from the mouthpiece of each inhaler and over the trachea of each participant. Each participant's PIFR was also recorded for each of the four inhalers. Results showed that gender and anthropometric features have the potential to influence the spectral properties of ambient and tracheal inspiratory inhaler sounds. It was also observed that males achieved statistically significantly higher PIFRs in each inhaler in comparison to females (p<;0.05). Acoustic features were found to be significantly different across inhalers suggesting that acoustic features are modulated by the inhaler design and its internal resistance to airflow.

PURPOSE/OBJECTIVE:Some patients are unable to generate the peak inspiratory flow rate (PIFR) necessary to de-agglomerate drug particles from dry powder inhalers (DPIs). In this study we tested the hypothesis that the acoustic parameters of an inhalation are related to the PIFR and hence reflect drug delivery. METHODS:A sensitivity analysis of the relationship of the acoustics of inhalation to simultaneously recorded airflow, in a cohort of volunteers (n = 92) was performed. The Next Generation Impactor (NGI) was used to assess in vitro drug delivery from salmeterol/fluticasone and salbutamol Diskus™ DPIs. Fine particle fraction, FPF, (<5 μm) was measured at 30-90 l/min for 2-6 s and correlated with acoustically determined flow rate (IFRc). In pharmacokinetic studies using a salbutamol (200 μg) Diskus™, volunteers inhaled either at maximal or minimal effort on separate days. RESULTS:PIFRc was correlated with spirometrically determined values (R (2) = 0.88). In in vitro studies, FPF increased as both flow rate and inhalation duration increased for the salmeterol/fluticasone Diskus™ (Adjusted R (2) = 0.95) and was proportional to flow rate only for the salbutamol Diskus™ (Adjusted R (2) = 0.71). In pharmacokinetic studies, blood salbutamol levels measured at 20 min were significantly lower when PIFRc was less than 60 l/min, p < 0.0001. CONCLUSION/CONCLUSIONS:Acoustically-determined PIFR is a suitable method for estimating drug delivery and for monitoring inhalation technique over time.

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) affect over 400 million people and are incurable. The pressurized metered dose inhaler (pMDI) has been the most popular inhaler device in inhaled therapy in recent times. However the pMDIs require good coordination between inhaling and actuating the inhaler to deliver the aerosolized drug most effectively. Poor coordination can greatly reduce the amount of drug delivered to a patient and therefore reducing the control of respiratory disease symptoms. Acoustic methods have been recently employed to monitor inhaler technique quite effectively. This study employs a noninvasive acoustic method to detect actuation sounds in a portable monitoring device. A total of 158 actuation sounds were obtained from a group of healthy subjects (n=5) and subjects suffering from respiratory diseases (n=15). The developed algorithm generated an overall accuracy of 99.7% demonstrating that this method may have clinical potential to monitor pMDI actuation coordination. The informative feedback from this method may also be employed in clinical training to highlight patient actuation technique.

Drug delivery from a Dry Powder Inhaler (DPI) is dependent on the peak inspiratory flow rate (PIFR) generated. Currently available methods for estimating PIFR from most DPIs are limited and mainly rely on subjective assessment. We aim to show that spirometric and Diskusâ„¢ PIFR and Inspiratory Vital Capacity (IVC) are related to the underlying respiratory condition and that spirometric PIFR can be used to assess whether Diskusâ„¢ PIFR will be adequate when using this DPI. Healthy volunteers and patients with asthma, COPD, neuromuscular disease and non-respiratory disorders were recruited (n = 85). Demographics and baseline lung function by spirometry were recorded. Flow and volume readings were taken while patients used a Diskusâ„¢ DPI, housed in an airtight container connected to a spirometer. T-tests were performed to compare mean spirometric and Diskusâ„¢ PIFR/ IVC between groups. Stepwise regression analysis of Diskusâ„¢ PIFR versus spirometric PIFR, spirometric IVC, age, gender, condition, BMI, FEV1 and FVC was performed. The Diskusâ„¢ PIFR for the COPD and Neuromuscular Disease group was more than 10 L/min lower than the Healthy or Asthma groups (p < 0.05). The mean spirometric and Diskusâ„¢ IVC of the Healthy group was significantly (>0.75 L) higher than the mean for the other three groups (p < 0.05). Diskusâ„¢ PIFR was moderately correlated with spirometric PIFR and age (Adjusted R(2) = 0.58, p < 0.0001). PIFR generated using a Diskusâ„¢ DPI is dependent on the underlying disease and age. A spirometric PIFR of less than 196 L/min should prompt further investigation into the suitability of a patient for a Diskusâ„¢ DPI, with possible consideration of alternate devices.

RATIONALE/BACKGROUND:Poor adherence to inhaler use can be due to poor temporal and/or technique adherence. Up until now there has been no way of reliably tracking both these factors in everyday inhaler use. OBJECTIVES/OBJECTIVE:This paper introduces a device developed to create time stamped acoustic recordings of an individual's inhaler use, in which empirical evidence of temporal and technique adherence in inhaler use can be monitored over time. The correlation between clinical outcomes and adherence, as determined by this device, was compared for temporal adherence alone and combined temporal and technique adherence. FINDINGS/RESULTS:The technology was validated by showing that the doses taken matched the number of audio recordings (r2 = 0.94, p<0.01). To demonstrate that audio analysis of inhaler use gives objective information, in vitro studies were performed. These showed that acoustic profiles of inhalations correlated with the peak inspiratory flow rate (r2 = 0.97, p<0.01), and that the acoustic energy of exhalations into the inhaler was related to the amount of drug removed. Despite training, 16% of participants exhaled into the mouthpiece after priming, in >20% of their inhaler events. Repeated training reduced this to 7% of participants (p = 0.03). When time of use was considered, there was no evidence of a relationship between adherence and changes in AQLQ (r2 = 0.2) or PEFR (r2 = 0.2). Combining time and technique the rate of adherence was related to changes in AQLQ (r2 = 0.53, p = 0.01) and PEFR (r2 = 0.29, p = 0.01). CONCLUSIONS:This study presents a novel method to objectively assess how errors in both time and technique of inhaler use impact on clinical outcomes. TRIAL REGISTRATION/BACKGROUND:EudraCT 2011-004149-42.